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disease-related GI signs and symptoms. This may prove instrumental in recognizing these manifestations in
[36]
patients participating in clinical trials, as well as those in real-world clinical settings .
Stool studies are useful in the diagnostic assessment for Fabry patients with diarrhea, and the Sitzmarker test
[5]
serves as a reliable tool for evaluating gut transit time . Radiological studies including Doppler scanning or
angiography are instrumental in probing GI motility and blood flow, particularly when vascular
compromise is a consideration . To assess upper GI symptoms such as nausea, a gastric emptying scan
[5,9]
offers insights into motility patterns, while a breath test proves beneficial in identifying bacterial overgrowth
secondary to impaired gastric motility and delayed emptying . Additionally, biopsies may be warranted for
[10]
histological studies aimed at confirming GI involvement. This entails analyzing evidence of GL-3 deposits in
enlarged and vacuolated neurons, as well as in endothelial and vascular smooth muscle cells. These biopsies
[12]
also serve to rule out potential comorbidities .

TREATMENT
Specific therapy
Enzyme replacement therapy (ERT) with either agalsidase beta (1 mg/kg every other week) or agalsidase alfa
(0.2 mg/kg EOW) has been available for the treatment of Fabry patients since 2001 [37,38] . The initial study
designed to evaluate the positive impact of ERT on gastrointestinal symptoms was reported by
[39]
Dehout et al. . In total, eleven cases were enrolled and a significant reduction in both the severity and
frequency of abdominal pain and diarrhea was obtained. In a study by Wraith et al., encompassing 14 male
and 2 female pediatric patients aged 8 to 16, who received agalsidase beta treatment over 48 weeks, patient
reports of post-prandial pain, nausea, and vomiting exhibited a consistent decline over time on treatment.
By week 24, statistically significant improvements were observed . Additionally, utilizing the Fabry
[40]
Outcome Survey database, Hoffmann et al. observed a reduction in the prevalence of gastrointestinal
symptoms following agalsidase alfa at both 12 and 24 months .
[41]
The Fabry Registry is a multicenter and observational program designed to monitor the natural history and
[42]
treatment outcomes of patients with FD . In an effort to gain deeper insights into the enduring effects of
agalsidase beta treatment on gastrointestinal symptoms, data from the Fabry Registry for the years 2018 and
2020 were analyzed for female and male patients, respectively [43,44] . The outcome measures in 168 females
analyzed in the Fabry registry were self-reported gastrointestinal symptoms at both baseline and their last
follow-up (with a prerequisite of receiving agalsidase beta treatment for a minimum of 2.5 years). Baseline
pre-treatment abdominal pain was reported by 45% of females and diarrhea by 39%. At last follow-up, 31%
reported abdominal pain and 27% diarrhea . In males, the Fabry Registry analysis was stratified by
[43]
phenotype. Classic male patients reported GI symptoms more frequently at baseline vs. later-onset
phenotype. As compared with baseline, significantly fewer classic patients reported abdominal pain and
diarrhea after a median of 4.7 and 5.5 years of follow-up, respectively. While the reduction in reports among
males with later-onset phenotypes was statistically non-significant, it still indicated an improvement post-
treatment . The results of this Fabry Registry analysis suggest that on sustained treatment with agalsidase
[44]
beta, both abdominal pain and diarrhea improved in patients with FD.

Furthermore, it is worth noting that the dosage or specific compound utilized may influence the outcome of
gastrointestinal (GI) symptoms. Notably, patients who received a reduced dose of agalsidase beta (ranging
from 0.3 to 0.5 mg/kg) or those who transitioned from agalsidase beta to agalsidase alfa during the global
[45]
shortage of agalsidase beta reported an increase in gastrointestinal pain . Unfortunately, in many of these
studies, despite documented improvement, some patients continue to experience GI symptoms even after a
substantial period of enzyme replacement therapy (ERT) intervention. In certain instances, patients may